Core 2 1-6-N-glucosaminyltransferase-I in diabetic atherosclerosis

Using C2GlcNAcT-I-/- mice, we have recently demonstrated the importance of C2GlcNAcT-I in hypercholesterolemia-induced atherosclerosis. C2GlcNAcT-I activity is upregulated by high level of glucose and involved in the development of retinopathy in diabetic patients. Accelerated atherosclerosis is one of major fatal complications for patients with diabetes. It is very likely that C2GlcNAcT-I play a greater role in diabetic-induced atherosclerosis than in hypercholesterolemia-induced atherosclerosis. However, so far, this possibility has not been tested. We have crossed C2GlcNAcT-I-/- mice with apoE-/- mice to generate C2GlcNAcT-I-/-/apoE-/- mice. ApoE-/- and C2GlcNAcT-I-/-/apoE-/- mice will be rendered type 1 diabetes via intraperitoneal injections of streptozotocin. In addition, mice will be fed a high fed diet to develop type 2 diabetes. We will employ several unique models, including in vitro, ex vivo and in vivo, to determine the role of C2GlcNAcT-I in the homing ability of diabetic monocytes, the adhesiveness of diabetic arterial endothelium, as well as the formation of atherosclerotic lesions in diabetic mice. This study will have significant implications for the inhibition of C2GlcNAcT-I as an approach in the prevention and treatment of accelerated atherosclerosis occurring in diabetic patients. (AHA Program: Grant-in-Aid)